The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Opioids are widely used in medicine as analgesics, for example in the treatment of patients with severe pain, chronic pain, or to manage pain after surgery. Indeed, it is presently accepted that, in the palliation of more severe pain, no more effective therapeutic agents exist.
The term “opioid” is typically used to describe an API that activates opioid receptors, which are found in the brain, the spinal cord and the gut. Three classes of opioids exist:
(a) naturally-occurring opium alkaloids. These include morphine and codeine;
(b) compounds that are similar in their chemical structure to the naturally-occurring opium alkaloids. These so-called semi-synthetics are produced by chemical modification of the latter and include the likes of diamorphine (heroin), oxycodone and hydrocodone; and
(c) truly synthetic compounds such as fentanyl and methadone. Such compounds may be completely different in terms of their chemical structures to the naturally-occurring compounds.
Of the three major classes of opioid receptors (μ, κ and δ), opioids' analgesic and sedative properties mainly derives from agonism at the μ receptor.
Opioid analgesics are used to treat the severe, chronic pain of terminal cancer, often in combination with non-steroid anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. during recovery from surgery). Further, their use is increasing in the management of chronic, non-malignant pain.
Optimal management of chronic pain requires around-the-clock coverage. In this respect, opioid-requiring cancer patients are usually given slow-release opiates (slow-release morphine, oxycodone or ketobemidone, or transdermal fentanyl). DDSs that are capable of providing a sustained release of such APIs allow the patient to obtain this baseline analgesia with a minimal number of doses per day. This in turn improves patient compliance and minimizes interference with the individual's lifestyle and therefore quality of life.
Transdermal fentanyl DDSs comprise patches (e.g. DURAGESIC®) that are applied to the skin to deliver that potent opioid analgesic, which is slowly absorbed through the skin into systemic circulation. Pain may be relieved for up to three days from a single patch application.
However, such patches do not provide for a constant plasma level of API over the entire application period. This defect is an inevitable consequence of the fact that transdermal administration of fentanyl gives rise to the formation of a fentanyl depot in skin tissue. Serum fentanyl concentrations increase gradually following initial application of a patch, generally levelling off between 12 and 24 hours before reaching a saturation point, whereafter absorption of API remains relatively constant, with some fluctuation, for the remainder of the 72-hour application period.
Furthermore, firstly, in the design of sustained release DDSs with extremely potent APIs, such as opioids, the risk for “dose dumping” has to be eliminated in view of the risk of severe and, on occasions, lethal side effects. Secondly, a perennial problem with potent opioid analgesics such as fentanyl is one of abuse by drug addicts. Addicts normally abuse DDSs by one or more of the following processes:
(i) extracting a large quantity of API from that DDS using acid and/or alcohol into solution, which is then injected intravenously. With most commercially-available DDSs, this can be done relatively easily, which renders them unsafe or “abusable”;
(ii) heating (and then smoking);
(iii) crushing of tablet (and then snorting); and/or
(iv) in the case of a patch, making a tea (and then drinking).
Thus, there is a clear unmet clinical need for an effective DDS that is capable of treating e.g. severe pain via a sustained release of APIs (such as opioid analgesics), whilst at the same time minimising the possibility of dose dumping and/or abuse by addicts.
Ceramics are becoming increasingly useful to the medical world, in view of the fact they are durable and stable enough to withstand the corrosive effect of body fluids.
For example, surgeons use bioceramic materials for repair and replacement of human hips, knees, and other body parts. Ceramics also are being used to replace diseased heart valves. When used in the human body as implants or even as coatings to metal replacements, ceramic materials can stimulate bone growth, promote tissue formation and provide protection from the immune system. Dental applications include the use of ceramics for tooth replacement implants and braces.
Ceramics are also known to be of potential use as fillers or carriers in controlled-release DDSs. See, for example, EP 947 489 A, U.S. Pat. No. 5,318,779, WO 2008/118096, Lasserre and Bajpai, Critical Reviews in Therapeutic Drug Carrier Systems, 15, 1 (1998), Byrne and Deasy, Journal of Microencapsulation, 22, 423 (2005) and Levis and Deasy, Int. J. Pharm., 253, 145 (2003).
In particular, Rimoli et al, J. Biomed. Mater. Res., 87A, 156 (2008), US patent application 2006/0165787 and international patent applications WO 2006/096544, WO 2006/017336 and WO 2008/142572 all disclose various ceramic substances for controlled release of APIs, with the latter two documents being directed in whole or in part to opioid analgesics, with the abuse-resistance being imparted by the ceramic structures' mechanical strength.
Methods employed in these documents typically involve the incorporation of APIs into pre-formed porous ceramic materials comprising e.g. porous halloysite, kaolin, titanium oxide, zirconium oxide, scandium oxide, cerium oxide and yttrium oxide. In this respect, loading of API typically comprises soaking, extrusion-spheronization and/or cryopelletization in the prior art.
Ceramic carriers are also optionally mixed with traditional excipients to form tablets or the like. It is known to be difficult to infuse drug into a pre-formed porous ceramic structure. Indeed, in the case of opioids, it is considered that such API-incorporation methodology will not enable the loading of sufficient API to provide appropriate doses for effective therapeutic pain management, over a prolonged time, given that infusion of API into preformed pores is a difficult thing to do.
In WO 2008/142572, drugs are incorporated during the formation of a ceramic carrier using chemically bonded ceramics, such as calcium aluminate or calcium silicate. Although this leads to a higher amount of drug incorporation than is typically the case for preformed ceramic materials, the mechanical strength and the chemical stability of the ceramic structures described in WO 2008/142572 is, relatively speaking, limited, especially in acidic conditions.
There is thus a presently unmet clinical need for a DDS that imparts sustained release of potent APIs over extended periods of time combined with a low risk of dose dumping and/or drug diversion (abuse).